Sickle cell anemia is one of the most common genetic diseases worldwide, estimated to affect on in six-hundred African American births. During the past decade, great strides have been in management of patients by treatment modalities that are primarily directed towards and treatment of complications. Important advances have been made on the prevention of early death from pneumonia and other infections with early diagnosis and prophylactic antibody therapy. Frequent transfusions have also reduced incidence of recurring cerebrovascular episodes. Concerted efforts are being made to find agents that stimulate fetal hemoglobin synthesis. Hydroxyurea is found to decrease the frequency of painful crisis and hospitalization, and recent studies with butyrates appear to be promising. This program project is a continuation of our research on gene therapy strategies of sickle cell disease. It utilizes several approaches to improve the possibility of gene therapy in sickle cell anemia. From work of the past project years, we have succeeded in building an improved mouse model of sickle cell anemia that may more closely mimic the human condition Because these mice have difficulty in surviving in utero and neonatal period, we are planning various strategies to improve their survival. We also plan experiments to test the in utero delivery of genes, as the liver hematopoiesis in the fetus is accessible. We will test viral vectors using the fetal mice and fetal monkey models. For transplantation of hematopoietic cells in utero or in the neonatal period without cytoabelation of the host, we will explore using the erythropoietin receptor to impart proliferative advantage to donor's hematopoietic cells. Finally, homologous recombination will be used to correct the sickle mutations. This program project will be supported by four cores, to provide administrative support, stem cells, viral vectors, and mouse breeding for the projects. The University of California at San Francisco has a long standing commitment to sickle cell anemia research, patient care, and education. This program project will work closely with the Northern California Comprehensive Sickle Cell Center, now in its twenty-second year of NHLBI funding.